1. Field of the Invention
The cephalosporins of the present invention in general possess the usual attributes of such compounds and are particularly useful in the treatment of bacterial infections.
2. Description of the Prior Art
U.K. Pat. No. 1,399,086 disclosed antibiotic compounds of the general formula ##STR2## (wherein R.sup.U is phenyl; naphthyl; thienyl; furyl, benzothienyl; benzofuryl; pyridyl or any of these groups substituted by halo (chloro, bromo, iodo or fluoro), hydroxy, lower alkyl, nitro, amino, loweralkylamino, diloweralkylamino, lower alkanoyl, lower alkanoylamino, lower alkoxy, lower alkylthio or carbamoyl; R.sup.b is lower alkyl; cycloalkyl containing 3-7 carbon atoms; carbocyclic or heterocyclic aryl lower alkyl or any of these groups substituted by hydroxy, carboxy, exterified carboxy, amido, cyano, alkanoyl, amino, substituted amino, halogen or lower alkoxy; and Y is selected from acetoxy; a group of formula ##STR3## WHERE R.sup.d and n are as defined in claim 19; a group of formula --SW where W is thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridyl, purinyl, pyridyl or pyrimidyl; an alkylthio group containing 1-4 carbon atoms; a group of formula --O.CO.R.sup.9 where R.sup.9 is an alkyl or alkenyl group containing 2-4 carbon atoms; the group --O.CO.NH.(CH.sub.2).sub.m D wherein m is an integer of from 1-4 and D is chlorine, bromine, iodine or fluorine; and azido) and non-toxic salts and esters thereof. Methods for the preparation of the starting acids used to form the 7-substituent, including their separation into syn and anti isomers, are also described therein and in U.K. Pat No. 1,404,221.
Presently issued U.S. Pat. Nos. 3,966,717 and 3,971,778 (with many nucleophilic substituents) contain at least part of the disclosure of U.K. Pat. No. 1,399,086 as does U.S. Pat. No. 3,974,153. See also Farmdoc abstracts 17270X and 19177X and 63415X (which also contains thiol substitution).
U.S. Pat. No. 3,974,153 claims compounds of the formula ##STR4## wherein R.sup.1 is furyl, thienyl or phenyl; and R.sup.a is C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or phenyl; and a physiologically acceptable salt thereof.
With reference to cephalosporins in which the acetoxy group in the 3-methyl substituent has been displaced by a thiol see U.S. Pat. No. 3,741,965 for a review of the older art. Specific disclosures of 3-substituents having the formula --CH.sub.2 --S--Het wherein Het is an aromatic, five membered ring containing at least two heterocyclic atoms and also having a substituent on that ring other than alkyl or aralkyl are found, for example, in U.S. Pat. Nos. 3,719,673, 3,757,014, 3,799,923 and 3,910,899. See also U.S. Pat. Nos. 3,516,997 and 3,819,623 and Farmdoc abstract 77919X.
U.S. Pat. Nos. 3,772,286, 3,812,116, 3,867,380, 3,912,728, 3,931,160 and 3,947,413 and U.K. Pat. No. 1,461,948 and Farmdoc (Derwent) abstracts 00145W, 22850W, 82150X, 68777X, 65694X, 02692X and 58433X make reference to 3-heterocyclicthiomethyl cephalosporins containing a number of substituents on the numerous heterocycles included but these references are completely general in nature and except for a few working examples include no physical constants, yields, methods of synthesis or the like and often do not even name the final compound. In most instances no method of preparation of the thiol itself is given or referred to and it often seems probable that they are novel compounds when the substituents are other than simple alkyl or aryl groups.
For examples of publications in the scientific literature see Ryan et al., Antimicrobial Agents and Chemotherapy, 9, 520-525 (1976) and O'Callaghan et al., ibid, 9, 511-519 (1976) and Norby et al., ibid, 9, 506-510 (1976) regarding cefuroxime and Leitner et al., ibid, 10(3), 426-435 (Sept. 1976) regarding BL-S786.
U.S. Pat. No. 3,819,623 discloses the conversion of the 2-mercapto-1,3,4-thiadiazole-5-acetic acid to 7-(1H-tetrazol-1-yl-acetamido)-3-(5-carboxymethyl-1,3,4-thiadiazol-2-ylthi omethyl)-3-cephem-4cephem-4-carboxylic acid and see also Farmdoc abstract 12921T.
Farmdoc abstract 18830X discloses acids of the formula ##STR5## (where R.sup.1 = acyl or H; R.sup.3 = H or methoxy; n = 1-9) and esters thereof. The compounds of the present invention are not described therein or in the full text of the corresponding patent. See also Farmdoc abstracts 01981X and 58433X and 52086X and 44686X and West Germany 2514322 (Farmdoc 69292W) and West Germany 2518582 (Ex. 6) (Farmdoc 74126W). See U.S. Pat. No. 3,989,694 and Farmdoc 01981X and Farmdoc 73990X for a similarly substituted triazole.